This stimulation, supplied via a pacemaker-like electronic device implanted in patients, yielded improvements over a carefully controlled three-month period and persisted during long-term follow-up averaging more than two years.
The trial results, published online March 18 in Epilepsia, may inform deliberations by the U.S. Food and Drug Administration over whether to approve the deep-brain-stimulation device for treatment of epilepsy in patients who get no benefit from existing therapies. The study’s first author, Robert Fisher, MD, PhD, of the Stanford University School of Medicine, has been researching deep-brain stimulation for more than two decades.
Epilepsy strikes one in 100 people, said Fisher, who is the Maslah Saul Professor in the Department of Neurology and Neurological Sciences and director of the Stanford Epilepsy Center. “It’s more common than people realize, because for centuries its stigma has led people not to talk about it.” According to the World Health Association, some 50 million people worldwide suffer from this condition.
Epilepsy is marked by recurrent seizures, or electrical storms in the brain that occur when electrical circuits in the brain — for reasons that are not clearly understood — begin firing spontaneously, rhythmically and uncontrollably. This can trigger disturbances in vision, hearing and behavior, as well as a loss of consciousness and injury-causing involuntary muscle movements.
Typically, epileptic seizures begin in a particular part of a patient’s brain — the location varies from patient to patient — and spread from there until they play themselves out. Patients experiencing these so-called partial-onset seizures make up about three-fifths of the population of people with epilepsy, said Fisher. Of those patients, about one-third respond poorly or not at all to currently approved anti-seizure drugs.
“There’s a false assumption out there that epilepsy is a ‘solved problem,’ but it’s not,” Fisher said. “Treatment failure among one-third of people with such a highly prevalent disease leaves a large number of people in great need of something better.”
In a multicenter trial led by Fisher, more than 100 adult subjects with partial-onset epilepsy had devices implanted whose output stimulated the left and right anterior nucleus of the thalamus, a relay station that lies deep within the brain. These patients’ conditions had not shown adequate improvement when treated by drugs currently approved for epilepsy or, in some cases, other therapies including stimulation of the vagus nerve and brain surgery. At the trial’s onset, the typical patient’s seizure frequency was about 20 per month.
With deep-brain stimulation, a battery-operated, pacemaker-like device delivers precisely measured and timed electrical impulses to the brain. The device is manufactured by Minneapolis-based Medtronic, Inc., which sponsored the trial. While this is the first definitive, randomized trial of DBS for epilepsy, it is approved and has been used by more than 70,000 people for Parkinson’s disease, other movement disorders and obsessive-compulsive disease.
After an initial three-month baseline period, DBS devices were surgically inserted under the skin of the chest wall, and electrical leads from the devices were threaded under the skin up the neck, behind the ear and through the skull to the thalamus. (At Stanford, this was done by study co-author Jaimie Henderson, MD, associate professor of neurosurgery.) This was followed by a one-month period during which patients recovered from the procedure. Interestingly, the mere positioning of the device in patients resulted in a 21 percent reduction in seizure frequencies, suggesting some degree of a placebo effect or beneficial response to the mere positioning of wires within the thalamus.
Then the devices were activated in one group of patients, while in an equal-sized group the device remained intact, but inactive. This part of the trial was blinded: Neither patients nor researchers (or caretakers) could tell which patients were receiving stimulation and which were not. Three months later, patients receiving stimulation were experiencing 40 percent fewer seizures than during the baseline period, while patients whose devices were not yet activated showed a 14.5 percent decrease — their seizure frequencies had begun to climb back up from the initial 21 percent drop during the recovery period.
Importantly, only 7 percent of patients in the DBS-active group experienced seizure-related injuries during the three-month blinded period, versus 26 percent in the control group.
In the second phase of the trial, the devices implanted in patients in the control group were also activated, so that all trial subjects were now receiving DBS. In those whose DBS devices weren’t activated until after the three-month blinded period, seizure rates began to decline immediately, eventually converging with rates among those whose devices had been active all along. This suggests, Fisher said, that DBS’s beneficial consequences were not merely a placebo effect or result of wire placement.
Nine months afterward — a full year after the initiation of DBS for the first group — patients’ seizure rates had decreased by 41 percent from baseline levels. Subjects were allowed to continue receiving DBS, and most chose to do so.
After two years of follow-up, seizure frequencies had dropped by 56 percent from baseline. While not all patients have yet been followed up for three years, those who have been tracked for that long experienced, on average, reductions of 68 percent — in other words, they are experiencing seizures only one-third as often now as they were before DBS. Fourteen patients were free of seizures for at least six months.
Fisher noted that for one study participant, activation of the DBS device initially triggered seizures every six minutes, in concert with the stimulation cycle. The patient experienced 210 mild seizures before the stimulation voltage was reduced by 20 percent, after which the patient experienced a seizure-rate decline compared with his baseline frequency. When the patient was included in the trial’s analysis, overall improvement for the DBS-active group vs. the control group showed statistical significance only during the third month of the blinded phase. Excluding this patient from the analysis yielded a statistically significant improvement for the entire three-month blinded phase, Fisher said.
Adverse effects experienced among the 110 patients were mainly limited to infection at the site of implantation, misplaced electrical leads that had to be repositioned or tingling sensations. While there were five deaths, none were attributable to DBS. More patients whose devices were immediately activated reported depression or loss of memory during the blinded period of the trial than did those in the control group, although objective assessments revealed no significant differences.
Fisher has no financial ties with Medtronic, the trial’s sponsor. Henderson has received consulting fees from the company.
Information about the Department of Neurology and Neurological Sciences, which supported the work, is available at http://neurology.stanford.edu/.